CN106554365B - A kind of preparation process and its application of entecavir midbodies - Google Patents
A kind of preparation process and its application of entecavir midbodies Download PDFInfo
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- CN106554365B CN106554365B CN201611005027.5A CN201611005027A CN106554365B CN 106554365 B CN106554365 B CN 106554365B CN 201611005027 A CN201611005027 A CN 201611005027A CN 106554365 B CN106554365 B CN 106554365B
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- entecavir
- organic peroxide
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- 229960000980 entecavir Drugs 0.000 title claims abstract description 28
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000001451 organic peroxides Chemical class 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical group C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- BIISIZOQPWZPPS-UHFFFAOYSA-N 2-tert-butylperoxypropan-2-ylbenzene Chemical compound CC(C)(C)OOC(C)(C)C1=CC=CC=C1 BIISIZOQPWZPPS-UHFFFAOYSA-N 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000010791 quenching Methods 0.000 claims description 8
- 230000000171 quenching effect Effects 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 3
- 239000004210 ether based solvent Substances 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000002829 reductive effect Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 208000002672 hepatitis B Diseases 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- -1 entecavir compound Chemical class 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- OKIRBHVFJGXOIS-UHFFFAOYSA-N 1,2-di(propan-2-yl)benzene Chemical compound CC(C)C1=CC=CC=C1C(C)C OKIRBHVFJGXOIS-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- KRDXTHSSNCTAGY-UHFFFAOYSA-N 2-cyclohexylpyrrolidine Chemical compound C1CCNC1C1CCCCC1 KRDXTHSSNCTAGY-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 238000006228 Dieckmann condensation reaction Methods 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010053961 Mitochondrial toxicity Diseases 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical group CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 238000006946 Rubottom oxidation reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 208000016350 chronic hepatitis B virus infection Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- DYDLEGFFUXTDAD-LURJTMIESA-N dimethyl (3s)-3-hydroxyhexanedioate Chemical compound COC(=O)CC[C@H](O)CC(=O)OC DYDLEGFFUXTDAD-LURJTMIESA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 231100000296 mitochondrial toxicity Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000002927 oxygen compounds Chemical class 0.000 description 1
- 125000005704 oxymethylene group Chemical group [H]C([H])([*:2])O[*:1] 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation processes of entecavir midbodies and the intermediate to prepare the application in Entecavir, which includes: that by formula S compound represented, haptoreaction obtains entecavir midbodies formula T compound represented in organic solvent with organic peroxide in the presence of NHPI；
Description
Technical field
The invention belongs to technical field of medicine synthesis, are related to the preparation process and its application of a kind of entecavir midbodies.
Background technique
Entecavir, its chemical name is 2- amino -9- [(1s, 3s, 4s) -4- hydroxyl -3- methylol -2- methylenes penta
Base] -1,9- hydrogen -6-H- purine-6-one-hydrate, which is researched and developed by Bristol-MyersSquibb company, is
It is a kind of effective, the deoxyguanosine analog of selective depression hepatitis B replication, for treating hepatitis B.
In vitro test shows that Entecavir is more more effective than other nucleoside analogs.Animal model and Human Clinical Study are the results show that grace
There is extremely strong inhibition hepatitis B replication for card Wei, the effect of serum-virus DNA level is reduced, to resistance to Lamivudine
Mutant strain is still effective, and has no apparent adverse reaction and mitochondrial toxicity.
A large amount of clinical tests show that it has directly reverse transcriptase in liver cell and hepatitis B virus DNA polymerase
Inhibiting effect has strong anti-virus ability, while the selectivity of the compound is relatively high, its cytotoxicity is anti-hepatitis virus
Active 1/8000, chronic hepatitis B can be effectively treated without interfering influenza virus and inhibition of HIV.And not due to its mechanism of action
Together, the drug resistance that generation is used for a long time is low.
Currently, there are 3.5 hundred million~400,000,000 Hepatitis B Virus Infections in the whole world, wherein there is nearly 1,000,000 patient to die of every year
Cirrhosis caused by HBV infection and liver cancer.There are about 1.2 hundred million HBV infection persons in China, account for the 1/3 of the world total, rank first in the world
Position, chronic hepatitis B patient 30,000,000, and also this number is just in rising trend at present.Chronic hepatitis B virus infection arrives
There are no the method that can be cured completely until now, patient needs long-term or in most cases needs to carry out virus throughout one's life
Inhibit.The clinical guidelines recommended therapy course for the treatment of is at least 1 year.The market of nucleoside medicine is occupied in the therapeutic agent of chronic hepatitis B
Rate is more than 80%.And in nucleoside medicine, Entecavir relied on its significant curative effect and good anti-drug resistance, from 2007 years
Since, having substituted Lamivudine becomes the anti-hepatic-B virus medicine of a line.Entecavir is ground by Bristol-Myers Squibb Co. of the U.S.
System, U.S. FDA are listed in approval on March 29th, 2005.It is total in acquisition state food pharmaceuticals administration on November 15th, 2005
Office's SFDA approval is in Discussion on Chinese Listed.The drug patent expired in 2008, and pharmaceutical chemistry brainstrust is for preparation method
Very more research is carried out, but structure is complicated due to entecavir compound, is also widely present in existing synthetic method
The problems such as step is long, yield is low, at high cost.
CN102593956B discloses a kind of preparation process of Entecavir, wherein the technique discloses one kind and passes through ring
The method that oxygen compound open loop introduces chiral hydroxyl group, shown in specific following route.The process requirement is urged using precious metal palladium
Agent and active magnesium metallic compound, at high cost, condition is harsh.In addition, due to the space bit of 2- substitution Oxymethylenes
Inhibition effect, so that the epoxide of target configuration generates more difficult, yield reduction, industrialization difficulty is larger.This method must also
It must use chiral reagent that the transformation of compound hydroxyl configuration can just be obtained target compound.
CN105037363B discloses a kind of entecavir compound synthetic method, builds a house with (S) -3- hydroxyl adipic acid
Dimethyl ester is starting material, is reduced into hydroxyl at ketal, ester group by hydroxyl TBS protection, Dieckmann condensation reaction, ketone protection
Intermediate T is made at silyl enol ether, Rubottom oxidation reaction in base, hydroxyl protection, deprotection, ketone, and intermediate T is again through Wittg
Reaction, Mitsunobu reaction etc. obtain Entecavir, although this method provides a kind of method for being more suitable for industrialized production,
Yield is also improved, still, the production of this method especially intermediate T still have complex steps, reaction condition requirement height with
And the problem that yield is not high.Correlation step is as follows:
Summary of the invention
In view of there is also the above problems in the preparation process of Entecavir, the present invention is specifically proposed.
The present invention provides a kind of preparation process of entecavir midbodies (formula T compound represented), and the preparation process is anti-
It answers that step is shorter, yield is higher and the operation is more convenient, is suitble to amplification mass production.
The present invention provides the preparation process of entecavir midbodies, which includes:
By formula S compound represented, haptoreaction obtains grace in organic solvent with organic peroxide in the presence of NHPI
For card Wei intermediate formula T compound represented；
Under preferable case, the more specific process of the preparation process are as follows: by NHPI, formula S compound represented and have
Solvent is added in reaction kettle, is cooled to -10~10 DEG C, and the solution containing organic peroxide is added dropwise, and drop finishes, and keeps temperature
Stirring 2~5 hours, saturated ammonium chloride quenching reaction, methylene chloride extraction, washing recrystallize to obtain formula T compound represented,
Middle organic solvent is tetrahydrofuran or ether or other ether solvents etc..
In the present invention, NHPI is writing a Chinese character in simplified form for n-Hydroxyphthalimide, and addition can quickly cause above-mentioned anti-
It answers, and cooperates to obtain the product of enantiomeric excess or even single configuration with organic peroxide.
In the case of in the present invention, it is preferred to, the dosage molar ratio of formula S compound represented and NHPI, organic peroxide
For 1:0.05~0.25:1~3.In further preferred situation, the dosage of formula S compound represented and NHPI, organic peroxide
Molar ratio is 1:0.05~0.15:1.2~2.Inventor largely practices discovery, and organic peroxide dosage is greater than shown in formula S
When the dosage of 2 equivalent of compound and n-Hydroxyphthalimide is greater than 0.15 equivalent, reaction is not showed preferably,
It will increase the workload of cost and post-processing instead.
In the present invention, inventor, which also found, influences the selectivity of product configuration using the peroxide of different structure
Larger, under preferable case, the organic peroxide is cumyl peroxide and/or t-butylcumylperoxide.This
Under part, can be highly selective obtain the target compound of single configuration.Under preferable case, organic peroxide such as peroxidating
Diisopropylbenzene (DIPB) or t-butylcumylperoxide are instilled in reaction system in the form of its solution, such as instill peroxidating diisopropyl
The diethyl ether solution or peroxide of the tetrahydrofuran solution of the diethyl ether solution of benzene or cumyl peroxide, t-butylcumylperoxide
Change the tetrahydrofuran solution of tert-butyl cumyl peroxide.
In the present invention, the influence to reaction such as moisture and oxygen in external environment in order to prevent, under preferable case, system
Standby technique carries out under nitrogen protection.Reaction of the invention can carry out post-reaction treatment, example according to the means of this field routine
Such as washing, filtering, crystallization.It can be monitored according to conventional means during every step, such as LCMS, GCMS, TLC
Deng.In other no specified otherwises, room temperature as used in the present invention refers to 23 ± 2 DEG C.
The present invention also provides a kind of preparation processes of Entecavir, the grace that wherein technique is prepared by above-mentioned preparation process
It is starting material for card Wei intermediate (formula T compound represented), it is anti-through Wittg reaction, Mitsunobu again by intermediate T
Answer, dehydroxylation protecting group and hydrolysis obtain Entecavir, these steps can with reference to method in the prior art carry out, such as
Related operating method in CN105037363B, is hereby incorporated and is incorporated herein.
Three-dimensional hydroxyl is directly introduced ring using one-step method by the preparation process of entecavir midbodies provided by the invention
Pentane ring, yield greatly improve, and selectively obtain R anomeric product, obtain target mesh without chiral resolution or purifying
Compound is marked, the operation is more convenient, effectively reduces the workload in Entecavir preparation process.Entecavir midbodies formula T
The yield of compound represented significantly improves, and has ensured the raw materials requirement of Entecavir.
Specific embodiment
The present invention is described in detail combined with specific embodiments below.Following embodiment will be helpful to the technology of this field
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill of this field
For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention
Protection scope.
Embodiment 1
Under nitrogen protection, by NHPI 0.81g (5mmol), formula S compound represented 35.9g (100mmol) and 100ml
Anhydrous tetrahydro furan is added in 250ml reaction kettle, is stirred and is cooled to 5 DEG C, and the second of cumyl peroxide is then added dropwise
The tetrahydrofuran solution (containing cumyl peroxide 40.56g) of ethereal solution or cumyl peroxide, drop finish, and keep temperature
Stirring 3 hours monitors that reaction terminates, and saturated ammonium chloride quenching reaction, methylene chloride extraction, washing three are added in ice bath
It is secondary, merge organic phase, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and petroleum ether recrystallizes to obtain formula T compound represented 32.37g, receives
Rate 86.40%.
1HNMR(400MHz,CDCl3)δ5.51(brs,1H),4.40-4.35(m,2H),3.51(d,1H),3.28(m,
1H),2.79-2.75(m,1H),2.19-1.98(m,1H),1.82(d,1H),0.98(s,9H),0.96(s,9H),0.12(m,
12H)。
Embodiment 2
Under nitrogen protection, by NHPI 1.63g (10mmol), formula S compound represented 35.9g (100mmol) and
100ml anhydrous tetrahydro furan is added in 250ml reaction kettle, is stirred and is cooled to 0 DEG C, cumyl peroxide is then added dropwise
Diethyl ether solution (containing cumyl peroxide or t-butylcumylperoxide 54.07g), drop finishes, and keeps temperature stirring 2 small
When, it monitors that reaction terminates, saturated ammonium chloride quenching reaction, methylene chloride extraction is added in ice bath, washing three times, is associated with
Machine phase, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and petroleum ether recrystallizes to obtain formula T compound represented 32.32g, yield 86.27%.
Embodiment 3
Under nitrogen protection, by NHPI 2.45g (15mmol), formula S compound represented 35.9g (100mmol) and
100ml anhydrous tetrahydro furan is added in 500ml reaction kettle, is stirred and is cooled to 0 DEG C, and it is different that tert-butyl peroxide is then added dropwise
The diethyl ether solution (containing cumyl peroxide or t-butylcumylperoxide 25.0g) of propyl benzene, drop finish, and keep temperature stirring
It 4 hours, monitors that reaction terminates, saturated ammonium chloride quenching reaction, methylene chloride extraction is added in ice bath, washing three times, is closed
And organic phase, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and petroleum ether recrystallizes to obtain formula T compound represented 31.89g, yield
85.12%.
Embodiment 4
Under nitrogen protection, by NHPI 3.26g (20mmol), formula S compound represented 35.9g (100mmol) and
100ml anhydrous tetrahydro furan is added in 250ml reaction kettle, is stirred and is cooled to -10 DEG C, and peroxidating diisopropyl is then added dropwise
The tetrahydrofuran solution (containing cumyl peroxide or t-butylcumylperoxide 27.04g) of benzene, drop finish, and keep temperature
Stirring 5 hours monitors that reaction terminates, and saturated ammonium chloride quenching reaction, methylene chloride extraction, washing three are added in ice bath
It is secondary, merge organic phase, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and petroleum ether recrystallizes to obtain formula T compound represented 30.51g, receives
Rate 81.43%.
Embodiment 5
Under nitrogen protection, by NHPI 4.08g (25mmol), formula S compound represented 35.9g (100mmol) and
100ml anhydrous tetrahydro furan is added in 500ml reaction kettle, is stirred and is cooled to -5 DEG C, tert-butyl peroxide is then added dropwise
The diethyl ether solution (containing cumyl peroxide or t-butylcumylperoxide 62.49g) of isopropylbenzene, drop finish, and keep temperature
Stirring 3 hours monitors that reaction terminates, and saturated ammonium chloride quenching reaction, methylene chloride extraction, washing three are added in ice bath
It is secondary, merge organic phase, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and petroleum ether recrystallizes to obtain formula T compound represented 31.75g, receives
Rate 84.75%.
Comparative example
Under nitrogen protection, formula S compound represented 35.9g (100mmol) and 100ml anhydrous tetrahydro furan are added to
It in 250ml reaction kettle, stirs and is cooled to 5 DEG C, diethyl ether solution or the peroxidating two that cumyl peroxide is then added dropwise are different
The tetrahydrofuran solution (containing cumyl peroxide 40.56g) of propyl benzene, drop finish, and temperature is kept to stir 5 hours, monitor anti-
It answers raw material (formula S compound represented) no longer to change, saturated ammonium chloride quenching reaction is added in ice bath, methylene chloride extracts,
Washing three times, merges organic phase, and anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and column chromatographs to obtain formula T compound represented 12.25g, receives
Rate 32.70%.
1HNMR(400MHz,CDCl3)δ5.51(brs,1H),4.40-4.35(m,2H),3.51(d,1H),3.28(m,
1H),2.79-2.75(m,1H),2.19-1.98(m,1H),1.82(d,1H),0.98(s,9H),0.96(s,9H),0.12(m,
12H)。
Claims (3)
1. a kind of preparation process of entecavir midbodies, which is characterized in that the preparation process includes:
Formula S compound represented is connect in organic solvent with organic peroxide in the presence of n-Hydroxyphthalimide
Touching reaction obtains entecavir midbodies formula T compound represented；The more specific process of the preparation process are as follows: by N- hydroxyl
Phthalimide, formula S compound represented and organic solvent are added in reaction kettle, are cooled to -10~10 DEG C, are added dropwise
Solution containing organic peroxide, drop finish, and temperature is kept to stir 2~5 hours, saturated ammonium chloride quenching reaction, methylene chloride
Extraction, washing, recrystallizes to obtain formula T compound represented, and wherein organic solvent is tetrahydrofuran or ether or other ether solvents；
Formula S compound represented and n-Hydroxyphthalimide, the dosage molar ratio of organic peroxide are 1:0.05~0.25:
1~3；The organic peroxide is cumyl peroxide and/or t-butylcumylperoxide；
2. preparation process according to claim 1, which is characterized in that formula S compound represented and N- hydroxyl O-phthalic
Acid imide, organic peroxide dosage molar ratio be 1:0.05~0.15:1.2~2.
3. preparation process according to claim 1 or 2, which is characterized in that preparation process carries out under nitrogen protection.
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